PROJECT SUMMARY Perception of sensory information by the brain is highly dependent on the information context, where responses to the most informative, or ?novel?, stimuli are selectively amplified. Novelty detection occurs early in the sensory cortex and is used for automatic focusing to stimuli that are most informative. Studies using the oddball paradigm with EEG and MEG show that deficits of novelty detection appear in patients with schizophrenia, suggesting its high importance for normal information processing and cognitive function. Because these methods are inherently low resolution, the neuronal circuit mechanism underlying novelty detection remains elusive. In this project I will be trained to use the Spatial Light Modulator for i) 3D volumetric two-photon calcium imaging, and ii) holographic optogenetics, to learn the population activity underlying novelty detection, and to interface with the cortex to manipulate contextual decision making and imprinting improved detection of novelty. First, (AIM 1) I will use two-photon holographic calcium imaging to record from hundreds of neurons simultaneously in awake mice undergoing a novelty detection task. Single trial trajectories of novelty detection neurons will be extracted to learn the true high dimensional activity structure of the population, and reveal how ongoing internal dynamics affect the sensory evoked response. Additionally, since novelty detection decomposes into preattentive and attention dependent components, we will train mice in a novelty detection behavior task to elucidate how individual trial trajectories correlate to attention and perception. Finally, we will repeat these experiments in a mouse model of schizophrenia, to reveal how ongoing activity and stimulus evoked single trial responses are affected in the disease phenotype. In the second part of this project (AIM 2) we will use cutting edge two-photon holographic methods for interfacing with the brain, to manipulate perception and control behavioral output during novelty detection behavior taks. Finally, we will use holographic ?training? methods to imprint stronger novelty detection circuits in schizophrenia model mice in an attempt to rescue the disease phenotype. These studies will yield i) true high dimensional neural activity underlying novelty detection and how it depends on the ongoing circuit activity, ii) key insights of how evoked single trial dynamics and ongoing activity is disrupted in the schizophrenia model, and iii) whether it is possible to use holographic training of novelty detection circuits to improve stimulus evoked response and rescue the disease phenotype. This work will provide the candidate with strong expertise in optics, large scale recordings and manipulation of neural activity, and analysis of neural circuit data, position him to pursue wide range of topics and tackle challenging question in the future career.